Calcium channels anticonvulsant action

Succinimides. Ethosuximide [77-67-8] C2H22NO2 (41) and the related succinknide, methsuximide [77-41-8] C22H23NO2 (42) are used in absence seizure treatment. Like the other anticonvulsants discussed, the mechanism of action of the succinirnides is unclear. Effects on T-type calcium channels and -ATPase activity have been reported (20). Ethosuximide has significant CNS and gastrointestinal (GI) side effect HabiUties (13). 

Alternate treatments. Mood-stabilization and control of manic or hy-pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively. 

The mechanism of action of anticonvulsants remains poorly characterized, both in terms of their anticonvulsant effects or their antimanic/mood stabilizing effects. They may even have multiple mechanisms of action. At the cell membrane, anticonvulsants appear to act on ion channels, including sodium, potassium, and calcium channels. By interfering with sodium movements through voltage-operated sodium... 

Other actions of some anticonvulsants include inhibition of the enzyme carbonic anhydrase, negative modulation of calcium channel activity, and actions on second messenger systems, including inhibition of phosphokinase C. Beyond the second messenger, there is the possibility that second messenger systems may be affected, analogously to what is hypothesized for lithium. 

FIGURE 7-27. Shown here is an icon of topiramate s pharmacologic actions. By interfering with calcium channels and sodium channels, topiramate is thought both to enhance the inhibitory actions of gamma aminobutyric acid (GABA) and to reduce the excitatory actions of glutamate. Topiramate is also a carbonic anhydrase inhibitor (CAI) and as such has independent anticonvulsant actions. 

Zonisamide is an anticonvulsant/sulfonamide that may exert its anticonvulsant effects through action at sodium and calcium channels. It is indicated as an adjunctive therapy in the treatment of partial seizures in adult epileptic patients. 

Many anticonvulsant drugs, as a major part of their mechanism of action, block the sodium channel, but other effective agents do not use this mechanism. Which of the following anticonvulsants has the ability to block T-calcium currents as its primary mechanism of action ... 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

Phenytoin is a hydantoin derivative like dantrolene and the oldest non-sedative anticonvulsant drug known. It alters sodium, potassium and calcium conductance across cell membranes thereby altering membrane potentials and amino acid and neurotransmitter concentrations (i.e. norepinephrine (noradrenaline), acetylcholine and GABA). Its major mode of action appears to be the blockade of sodium channels and e inhibition of the generation of repetitive action potentials (membrane stabilization) (see Chs 9 and 12). 

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